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Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Lipid Nanoparticles and Active Natural Compounds: A Perfect Combination for Pharmaceutical Applications

Author(s): Carmelo Puglia*, Rosario Pignatello, Virginia Fuochi, Pio Maria Furneri, Maria Rosaria Lauro, Debora Santonocito, Rita Cortesi and Elisabetta Esposito

Volume 26, Issue 24, 2019

Page: [4681 - 4696] Pages: 16

DOI: 10.2174/0929867326666190614123835

Price: $65

Abstract

Phytochemicals represent an important class of bioactive compounds characterized by significant health benefits. Notwithstanding these important features, their potential therapeutic properties suffer from poor water solubility and membrane permeability limiting their approach to nutraceutical and pharmaceutical applications. Lipid nanoparticles are well known carrier systems endowed with high biodegradation and an extraordinary biocompatible chemical nature, successfully used as platform for advanced delivery of many active compounds, including the oral, topical and systemic routes. This article is aimed at reviewing the last ten years of studies about the application of lipid nanoparticles in active natural compounds reporting examples and advantages of these colloidal carrier systems.

Keywords: Solid lipid nanoparticles, nanostructured lipid carriers, active natural compounds, drug delivery, stability, carrier systems.

« Previous
[1]
Vasisht, K.; Sharma, N.; Karan, M. Current perspective in the international trade of medicinal plants material: an update. Curr. Pharm. Des., 2016, 22(27), 4288-4336.
[http://dx.doi.org/10.2174/1381612822666160607070736] [PMID: 27281331]
[2]
Efferth, T.; Saeed, M.E.M.; Mirghani, E.; Alim, A.; Yassin, Z.; Saeed, E.; Khalid, H.E.; Daak, S. Integration of phytochemicals and phytotherapy into cancer precision medicine. Oncotarget, 2017, 8(30), 50284-50304.
[http://dx.doi.org/10.18632/oncotarget.17466] [PMID: 28514737]
[3]
Cardellina, J.H., II Challenges and opportunities confronting the botanical dietary supplement industry. J. Nat. Prod., 2002, 65(7), 1073-1084.
[http://dx.doi.org/10.1021/np0200515] [PMID: 12141880]
[4]
Raskin, I.; Ribnicky, D.M.; Komarnytsky, S.; Ilic, N.; Poulev, A.; Borisjuk, N.; Brinker, A.; Moreno, D.A.; Ripoll, C.; Yakoby, N.; O’Neal, J.M.; Cornwell, T.; Pastor, I.; Fridlender, B. Plants and human health in the twenty-first century. Trends Biotechnol., 2002, 20(12), 522-531.
[http://dx.doi.org/10.1016/S0167-7799(02)02080-2] [PMID: 12443874]
[5]
Sansone, F.; Mencherini, T.; Picerno, P.; D’Amore, M.; Aquino, R.P.; Lauro, M.R. Maltodextrin/pectin microparticles by spray-drying as carrier for nutraceutical extracts. J. Food Eng., 2011, 105, 468-476.
[http://dx.doi.org/10.1016/j.jfoodeng.2011.03.004]
[6]
Musthaba, S.M.; Ahmad, S.; Ahuja, A.; Ali, J.; Baboota, S. Nano approaches to enhance pharmacokinetic and pharmacodynamic activity of plant origin drugs. Curr. Nanosci., 2009, 5, 344-352.
[http://dx.doi.org/10.2174/157341309788921453]
[7]
Puglia, C.; Bonina, F. Lipid nanoparticles as novel delivery systems for cosmetics and dermal pharmaceuticals. Expert Opin. Drug Deliv., 2012, 9(4), 429-441.
[http://dx.doi.org/10.1517/17425247.2012.666967] [PMID: 22394125]
[8]
Puglia, C.; Lauro, M.R.; Tirendi, G.G.; Fassari, G.E.; Carbone, C.; Bonina, F.; Puglisi, G. Modern drug delivery strategies applied to natural active compounds. Expert Opin. Drug Deliv., 2017, 14(6), 755-768.
[http://dx.doi.org/10.1080/17425247.2017.1234452] [PMID: 27606793]
[9]
Müller, R.H.; Keck, C.M. Twenty years of drug nanocrystals: where are we, and where do we go? Eur. J. Pharm. Biopharm., 2012, 80(1), 1-3.
[http://dx.doi.org/10.1016/j.ejpb.2011.09.012] [PMID: 21971369]
[10]
Khosa, A.; Reddi, S.; Saha, R.N. Nanostructured lipid carriers for site-specific drug delivery. Biomed. Pharmacother., 2018, 103, 598-613.
[http://dx.doi.org/10.1016/j.biopha.2018.04.055] [PMID: 29677547]
[11]
Xing, H.; Wang, H.; Wu, B.; Zhang, X. Lipid nanoparticles for the delivery of active natural medicines. Curr. Pharm. Des., 2017, 23, 1-9.
[PMID: 29189139]
[12]
Severino, P.; Andreani, T.; Macedo, A.S.; Fangueiro, J.F.; Santana, M.H.A.; Silva, A.M.; Souto, E.B. Current State-of-Art and New Trends on Lipid Nanoparticles (SLN and NLC) for Oral Drug Delivery. J. Drug Deliv., 2012.2012750891
[http://dx.doi.org/10.1155/2012/750891] [PMID: 22175030]
[13]
Jalili-Nik, M.; Soltani, A.; Moussavi, S.; Ghayour-Mobarhan, M.; Ferns, G.A.; Hassanian, S.M.; Avan, A. Current status and future prospective of Curcumin as a potential therapeutic agent in the treatment of colorectal cancer. J. Cell. Physiol., 2018, 233(9), 6337-6345.
[http://dx.doi.org/10.1002/jcp.26368] [PMID: 29219177]
[14]
Ji, H.; Tang, J.; Li, M.; Ren, J.; Zheng, N.; Wu, L. Curcumin-loaded solid lipid nanoparticles with Brij78 and TPGS improved in vivo oral bioavailability and in situ intestinal absorption of curcumin. Drug Deliv., 2016, 23(2), 459-470.
[http://dx.doi.org/10.3109/10717544.2014.918677] [PMID: 24892628]
[15]
Wang, T.; Ma, X.; Lei, Y.; Luo, Y. Solid lipid nanoparticles coated with cross-linked polymeric double layer for oral delivery of curcumin. Colloids Surf. B Biointerfaces, 2016, 148, 1-11.
[http://dx.doi.org/10.1016/j.colsurfb.2016.08.047] [PMID: 27588376]
[16]
Ramalingam, P.; Ko, Y.T. Enhanced oral delivery of curcumin from N-trimethyl chitosan surface-modified solid lipid nanoparticles: pharmacokinetic and brain distribution evaluations. Pharm. Res., 2015, 32(2), 389-402.
[http://dx.doi.org/10.1007/s11095-014-1469-1] [PMID: 25082210]
[17]
Aditya, N.P.; Shim, M.; Lee, I.; Lee, Y.; Im, M.H.; Ko, S. Curcumin and genistein coloaded nanostructured lipid carriers: in vitro digestion and antiprostate cancer activity. J. Agric. Food Chem., 2013, 61(8), 1878-1883.
[http://dx.doi.org/10.1021/jf305143k] [PMID: 23362941]
[18]
Hazzah, H.A.; Farid, R.M.; Nasra, M.M.A.; Zakaria, M.; Gawish, Y.; El-Massik, M.A.; Abdallah, O.Y. A new approach for treatment of precancerous lesions with curcumin solid-lipid nanoparticle-loaded gels: in vitro and clinical evaluation. Drug Deliv., 2016, 23(4), 1409-1419.
[PMID: 26146889]
[19]
Hazzah, H.A.; Farid, R.M.; Nasra, M.M.A.; Hazzah, W.A.; El-Massik, M.A.; Abdallah, O.Y. Gelucire-Based Nanoparticles for Curcumin Targeting to Oral Mucosa: Preparation, Characterization, and Antimicrobial Activity Assessment. J. Pharm. Sci., 2015, 104(11), 3913-3924.
[http://dx.doi.org/10.1002/jps.24590] [PMID: 26202796]
[20]
Banerjee, S.; Padhye, S.; Azmi, A.; Wang, Z.; Philip, P.A.; Kucuk, O.; Sarkar, F.H.; Mohammad, R.M. Review on molecular and therapeutic potential of thymoquinone in cancer. Nutr. Cancer, 2010, 62(7), 938-946.
[http://dx.doi.org/10.1080/01635581.2010.509832] [PMID: 20924969]
[21]
Ong, Y.S.; Saiful Yazan, L.; Ng, W.K.; Abdullah, R.; Mustapha, N.M.; Sapuan, S.; Foo, J.B.; Tor, Y.S.; How, C.W.; Abd Rahman, N.; Zakarial Ansar, F.H. Thymoquinone loaded in nanostructured lipid carrier showed enhanced anticancer activity in 4T1 tumor-bearing mice. Nanomedicine (Lond.), 2018, 13(13), 1567-1582.
[http://dx.doi.org/10.2217/nnm-2017-0322] [PMID: 30028248]
[22]
Ng, W.K.; Saiful Yazan, L.; Yap, L.H.; Wan Nor Hafiza, W.A.; How, C.W.; Abdullah, R. Thymoquinone-loaded nanostructured lipid carrier exhibited cytotoxicity towards breast cancer cell lines (MDA-MB-231 and MCF-7) and cervical cancer cell lines (HeLa and SiHa). BioMed Res. Int., 2015.2015263131
[http://dx.doi.org/10.1155/2015/263131] [PMID: 25632388]
[23]
Singh, A.; Ahmad, I.; Akhter, S.; Jain, G.K.; Iqbal, Z.; Talegaonkar, S.; Ahmad, F.J. Nanocarrier based formulation of Thymoquinone improves oral delivery: stability assessment, in vitro and in vivo studies. Colloids Surf. B Biointerfaces, 2013, 102, 822-832.
[http://dx.doi.org/10.1016/j.colsurfb.2012.08.038] [PMID: 23104039]
[24]
Abdelwahab, S.I.; Sheikh, B.Y.; Taha, M.M.; How, C.W.; Abdullah, R.; Yagoub, U.; El-Sunousi, R.; Eid, E.E. Thymoquinone-loaded nanostructured lipid carriers: preparation, gastroprotection, in vitro toxicity, and pharmacokinetic properties after extravascular administration. Int. J. Nanomedicine, 2013, 8, 2163-2172.
[http://dx.doi.org/10.2147/IJN.S44108] [PMID: 23818776]
[25]
Alam, M.; Najmi, A.K.; Ahmad, I.; Ahmad, F.J.; Akhtar, M.J.; Imam, S.S.; Akhtar, M. Formulation and evaluation of nano lipid formulation containing CNS acting drug: molecular docking, in-vitro assessment and bioactivity detail in rats. Artif. Cells Nanomed. Biotechnol., 2018, 46(sup2), 46--57.
[http://dx.doi.org/10.1080/21691401.2018.1451873] [PMID: 29560744]
[26]
Khan, M.A.; Ali, R.; Parveen, R.; Najmi, A.K.; Ahmad, S. Pharmacological evidences for cytotoxic and antitumor properties of Boswellic acids from Boswellia serrata. J. Ethnopharmacol., 2016, 191, 315-323.
[http://dx.doi.org/10.1016/j.jep.2016.06.053] [PMID: 27346540]
[27]
Shi, F.; Zhao, J.H.; Liu, Y.; Wang, Z.; Zhang, Y.T.; Feng, N.P. Preparation and characterization of solid lipid nanoparticles loaded with frankincense and myrrh oil. Int. J. Nanomedicine, 2012, 7, 2033-2043.
[PMID: 22619540]
[28]
Murakami, A.; Takahashi, D.; Kinoshita, T.; Koshimizu, K.; Kim, H.W.; Yoshihiro, A.; Nakamura, Y.; Jiwajinda, S.; Terao, J.; Ohigashi, H. Zerumbone, a Southeast Asian ginger sesquiterpene, markedly suppresses free radical generation, proinflammatory protein production, and cancer cell proliferation accompanied by apoptosis: the α,β-unsaturated carbonyl group is a prerequisite. Carcinogenesis, 2002, 23(5), 795-802.
[http://dx.doi.org/10.1093/carcin/23.5.795] [PMID: 12016152]
[29]
Rahman, H.S.; Rasedee, A.; How, C.W.; Abdul, A.B.; Zeenathul, N.A.; Othman, H.H.; Saeed, M.I.; Yeap, S.K. Zerumbone-loaded nanostructured lipid carriers: preparation, characterization, and antileukemic effect. Int. J. Nanomedicine, 2013, 8, 2769-2781.
[http://dx.doi.org/10.2147/IJN.S45313] [PMID: 23946649]
[30]
Rahman, H.S.; Rasedee, A.; Abdul, A.B.; Zeenathul, N.A.; Othman, H.H.; Yeap, S.K.; How, C.W.; Hafiza, W.A. Zerumbone-loaded nanostructured lipid carrier induces G2/M cell cycle arrest and apoptosis via mitochondrial pathway in a human lymphoblastic leukemia cell line. Int. J. Nanomedicine, 2014, 9, 527-538.
[PMID: 24549090]
[31]
Rahman, H.S.; Rasedee, A.; Othman, H.H.; Chartrand, M.S.; Namvar, F.; Yeap, S.K.; Abdul Samad, N.; Andas, R.J.; Muhammad Nadzri, N.; Anasamy, T.; Ng, K.B.; How, C.W. Acute toxicity study of zerumbone-loaded nanostructured lipid carrier on BALB/c mice model. BioMed Res. Int., 2014.2014563930
[http://dx.doi.org/10.1155/2014/563930] [PMID: 25276798]
[32]
Rahman, H.S.; Rasedee, A.; How, C.W.; Zeenathul, N.A.; Chartrand, M.S.; Yeap, S.K.; Abdul, A.B.; Tan, S.W.; Othman, H.H.; Ajdari, Z.; Namvar, F.; Arulselvan, P.; Fakurazi, S.; Mehrbod, P.; Daneshvar, N.; Begum, H. Antileukemic effect of zerumbone-loaded nanostructured lipid carrier in WEHI-3B cell-induced murine leukemia model. Int. J. Nanomedicine, 2015, 10, 1649-1666.
[http://dx.doi.org/10.2147/IJN.S67113] [PMID: 25767386]
[33]
Parihar, V.K.; Prabhakar, K.R.; Veerapur, V.P.; Kumar, M.S.; Reddy, Y.R.; Joshi, R.; Unnikrishnan, M.K.; Rao, C.M. Effect of sesamol on radiation-induced cytotoxicity in Swiss albino mice. Mutat. Res., 2006, 611(1-2), 9-16.
[http://dx.doi.org/10.1016/j.mrgentox.2006.06.037] [PMID: 17045515]
[34]
Hsu, D.Z.; Chen, K.T.; Li, Y.H.; Chuang, Y.C.; Liu, M.Y. Sesamol delays mortality and attenuates hepatic injury after cecal ligation and puncture in rats: role of oxidative stress. Shock, 2006, 25(5), 528-532.
[http://dx.doi.org/10.1097/01.shk.0000209552.95839.43] [PMID: 16680019]
[35]
Kakkar, V.; Mishra, A.K.; Chuttani, K.; Chopra, K.; Kaur, I.P. Delivery of sesamol-loaded solid lipid nanoparticles to the brain for menopause-related emotional and cognitive central nervous system derangements. Rejuvenation Res., 2011, 14(6), 597-604.
[http://dx.doi.org/10.1089/rej.2011.1193] [PMID: 21978086]
[36]
Singh, N.; Khullar, N.; Kakkar, V.; Kaur, I.P. Sesamol loaded solid lipid nanoparticles: a promising intervention for control of carbon tetrachloride induced hepatotoxicity. BMC Complement. Altern. Med., 2015, 15, 142.
[http://dx.doi.org/10.1186/s12906-015-0655-y] [PMID: 25935744]
[37]
Singh, N.; Khullar, N.; Kakkar, V.; Kaur, I.P. Hepatoprotective effects of sesamol loaded solid lipid nanoparticles in carbon tetrachloride induced sub-chronic hepatotoxicity in rats. Environ. Toxicol., 2016, 31(5), 520-532.
[PMID: 25410024]
[38]
de Andrade Teles, R.B.; Diniz, T.C.; Costa Pinto, T.C.; de Oliveira Júnior, R.G.; Gama, E. Silva, M.; de Lavor, É.M.; Fernandes, A.W.C.; de Oliveira, A.P.; de Almeida Ribeiro, F.P.R.; da Silva, A.A.M.; Cavalcante, T.C.F.; Quintans Júnior, L.J.; da Silva Almeida, J.R.G. Flavonoids as Therapeutic Agents in Alzheimer’s and Parkinson’s Diseases: A Systematic Review of Preclinical Evidences. Oxid. Med. Cell. Longev., 2018.20187043213
[http://dx.doi.org/10.1155/2018/7043213] [PMID: 29861833]
[39]
Heo, H.J.; Lee, C.Y. Protective effects of quercetin and vitamin C against oxidative stress-induced neurodegeneration. J. Agric. Food Chem., 2004, 52(25), 7514-7517.
[http://dx.doi.org/10.1021/jf049243r] [PMID: 15675797]
[40]
Bagad, M.; Khan, Z.A. Poly(n-butylcyanoacrylate) nanoparticles for oral delivery of quercetin: preparation, characterization, and pharmacokinetics and biodistribution studies in Wistar rats. Int. J. Nanomedicine, 2015, 10, 3921-3935.
[PMID: 26089668]
[41]
Kumar, P.; Sharma, G.; Kumar, R.; Singh, B.; Malik, R.; Katare, O.P.; Raza, K. Promises of a biocompatible nanocarrier in improved brain delivery of quercetin: Biochemical, pharmacokinetic and biodistribution evidences. Int. J. Pharm., 2016, 515(1-2), 307-314.
[http://dx.doi.org/10.1016/j.ijpharm.2016.10.024] [PMID: 27756627]
[42]
Jain, A.S.; Shah, S.M.; Nagarsenker, M.S.; Nikam, Y.; Gude, R.P.; Steiniger, F.; Thamm, J.; Fahr, A. Lipid colloidal carriers for improvement of anticancer activity of orally delivered quercetin: formulation, characterization and establishing in vitro-in vivo advantage. J. Biomed. Nanotechnol., 2013, 9(7), 1230-1240.
[http://dx.doi.org/10.1166/jbn.2013.1636] [PMID: 23909137]
[43]
Rao, M.P.; Manjunath, K.; Bhagawati, S.T.; Thippeswamy, B.S. Bixin loaded solid lipid nanoparticles for enhanced hepatoprotection--preparation, characterisation and in vivo evaluation. Int. J. Pharm., 2014, 473(1-2), 485-492.
[http://dx.doi.org/10.1016/j.ijpharm.2014.07.027] [PMID: 25066077]
[44]
Zhou, X.; Zhang, X.; Ye, Y.; Zhang, T.; Wang, H.; Ma, Z.; Wu, B. Nanostructured lipid carriers used for oral delivery of oridonin: an effect of ligand modification on absorption. Int. J. Pharm., 2015, 479(2), 391-398.
[http://dx.doi.org/10.1016/j.ijpharm.2014.12.068] [PMID: 25556104]
[45]
Luan, J.; Zheng, F.; Yang, X.; Yu, A.; Zhai, G. Nanostructured lipid carriers for oral delivery of baicalin: in vitro and in vivo evaluation. Colloids Surf. A Physicochem. Eng. Asp., 2015, 466, 154-159.
[http://dx.doi.org/10.1016/j.colsurfa.2014.11.015]
[46]
Leonarduzzi, G.; Testa, G.; Sottero, B.; Gamba, P.; Poli, G. Design and development of nanovehicle-based delivery systems for preventive or therapeutic supplementation with flavonoids. Curr. Med. Chem., 2010, 17(1), 74-95.
[http://dx.doi.org/10.2174/092986710789957760] [PMID: 19941477]
[47]
Paolino, D.; Cosco, D.; Cilurzo, F.; Fresta, M. Innovative Drug Delivery Systems for the Administration of Natural Compounds. Curr. Bioact. Compd., 2007, 3, 262-277.
[http://dx.doi.org/10.2174/157340707783220301]
[48]
Bhushan, S.; Kakkar, V.; Pal, H.C.; Guru, S.K.; Kumar, A.; Mondhe, D.M.; Sharma, P.R.; Taneja, S.C.; Kaur, I.P.; Singh, J.; Saxena, A.K. Enhanced anticancer potential of encapsulated solid lipid nanoparticles of TPD: a novel triterpenediol from Boswellia serrata. Mol. Pharm., 2013, 10(1), 225-235.
[http://dx.doi.org/10.1021/mp300385m] [PMID: 23237302]
[49]
Jang, D.J.; Moon, C.; Oh, E. Improved tumor targeting and antitumor activity of camptothecin loaded solid lipid nanoparticles by preinjection of blank solid lipid nanoparticles. Biomed. Pharmacother., 2016, 80, 162-172.
[http://dx.doi.org/10.1016/j.biopha.2016.03.018] [PMID: 27133053]
[50]
Lollo, G.; Ullio-Gamboa, G.; Fuentes, E.; Matha, K.; Lautram, N.; Benoit, J.P. In vitro anti-cancer activity and pharmacokinetic evaluation of curcumin-loaded lipid nanocapsules. Mater. Sci. Eng. C, 2018, 91, 859-867.
[http://dx.doi.org/10.1016/j.msec.2018.06.014] [PMID: 30033321]
[51]
Puglia, C.; Frasca, G.; Musumeci, T.; Rizza, L.; Puglisi, G.; Bonina, F.; Chiechio, S. Curcumin loaded NLC induces histone hypoacetylation in the CNS after intraperitoneal administration in mice. Eur. J. Pharm. Biopharm., 2012, 81(2), 288-293.
[http://dx.doi.org/10.1016/j.ejpb.2012.03.015] [PMID: 22504443]
[52]
Yan, J.; Wang, Y.; Zhang, X.; Liu, S.; Tian, C.; Wang, H. Targeted nanomedicine for prostate cancer therapy: docetaxel and curcumin co-encapsulated lipid-polymer hybrid nanoparticles for the enhanced anti-tumor activity in vitro and in vivo. Drug Deliv., 2016, 23(5), 1757-1762.
[http://dx.doi.org/10.3109/10717544.2015.1069423] [PMID: 26203689]
[53]
Sou, K.; Inenaga, S.; Takeoka, S.; Tsuchida, E. Loading of curcumin into macrophages using lipid-based nanoparticles. Int. J. Pharm., 2008, 352(1-2), 287-293.
[http://dx.doi.org/10.1016/j.ijpharm.2007.10.033] [PMID: 18063327]
[54]
Coradini, K.; Friedrich, R.B.; Fonseca, F.N.; Vencato, M.S.; Andrade, D.F.; Oliveira, C.M.; Battistel, A.P.; Guterres, S.S.; da Rocha, M.I.; Pohlmann, A.R.; Beck, R.C. A novel approach to arthritis treatment based on resveratrol and curcumin co-encapsulated in lipid-core nanocapsules: In vivo studies. Eur. J. Pharm. Sci., 2015, 78, 163-170.
[http://dx.doi.org/10.1016/j.ejps.2015.07.012] [PMID: 26206297]
[55]
Loureiro, J.A.; Andrade, S.; Duarte, A.; Neves, A.R.; Queiroz, J.F.; Nunes, C.; Sevin, E.; Fenart, L.; Gosselet, F.; Coelho, M.A.; Pereira, M.C. Resveratrol and Grape Extract-loaded Solid Lipid Nanoparticles for the Treatment of Alzheimer’s Disease. Molecules, 2017, 22(2)E277
[http://dx.doi.org/10.3390/molecules22020277] [PMID: 28208831]
[56]
Kaur, L.P.; Guleri, T.K. Topical Gel: A Recent Approach for Novel Drug delivery. Asian J. Biomed. Pharm., 2013, 3(17), 1-5.
[57]
Summerlin, N.; Soo, E.; Thakur, S.; Qu, Z.; Jambhrunkar, S.; Popat, A. Resveratrol nanoformulations: challenges and opportunities. Int. J. Pharm., 2015, 479(2), 282-290.
[http://dx.doi.org/10.1016/j.ijpharm.2015.01.003] [PMID: 25572692]
[58]
Carlotti, M.E.; Sapino, S.; Ugazio, E.; Gallarate, M.; Morel, S. Resveratrol in solid lipid nanoparticles. J. Dispers. Sci. Technol., 2012, 33(4), 465-471.
[http://dx.doi.org/10.1080/01932691.2010.548274]
[59]
Caddeo, C.; Manconi, M.; Fadda, A.M.; Lai, F.; Lampis, S.; Diez-Sales, O.; Sinico, C. Nanocarriers for antioxidant resveratrol: formulation approach, vesicle self-assembly and stability evaluation. Colloids Surf. B Biointerfaces, 2013, 111, 327-332.
[http://dx.doi.org/10.1016/j.colsurfb.2013.06.016] [PMID: 23838200]
[60]
Friedrich, R.B.; Kann, B.; Coradini, K.; Offerhaus, H.L.; Beck, R.C.; Windbergs, M. Skin penetration behavior of lipid-core nanocapsules for simultaneous delivery of resveratrol and curcumin. Eur. J. Pharm. Sci., 2015, 78, 204-213.
[http://dx.doi.org/10.1016/j.ejps.2015.07.018] [PMID: 26215463]
[61]
Teskac, K.; Kristl, J. The evidence for solid lipid nanoparticles mediated cell uptake of resveratrol. Int. J. Pharm., 2010, 390(1), 61-69.
[http://dx.doi.org/10.1016/j.ijpharm.2009.10.011] [PMID: 19833178]
[62]
Aquino, R.; Morelli, S.; Tomaino, A.; Pellegrino, M.; Saija, A.; Grumetto, L.; Puglia, C.; Ventura, D.; Bonina, F. Antioxidant and photoprotective activity of a crude extract of Culcitium reflexum H.B.K. leaves and their major flavonoids. J. Ethnopharmacol., 2002, 79(2), 183-191.
[http://dx.doi.org/10.1016/S0378-8741(01)00379-8] [PMID: 11801380]
[63]
Li, H.; Zhao, X.; Ma, Y.; Zhai, G.; Li, L.; Lou, H. Enhancement of gastrointestinal absorption of quercetin by solid lipid nanoparticles. J. Control. Release, 2009, 133(3), 238-244.
[http://dx.doi.org/10.1016/j.jconrel.2008.10.002] [PMID: 18951932]
[64]
Chen-yu, G.; Chun-fen, Y.; Qi-lu, L.; Qi, T.; Yan-wei, X.; Wei-na, L.; Guang-xi, Z. Development of a quercetin-loaded nanostructured lipid carrier formulation for topical delivery. Int. J. Pharm., 2012, 430(1-2), 292-298.
[http://dx.doi.org/10.1016/j.ijpharm.2012.03.042] [PMID: 22486962]
[65]
Bose, S.; Du, Y.; Takhistov, P.; Michniak-Kohn, B. Formulation optimization and topical delivery of quercetin from solid lipid based nanosystems. Int. J. Pharm., 2013, 441(1-2), 56-66.
[http://dx.doi.org/10.1016/j.ijpharm.2012.12.013] [PMID: 23262430]
[66]
Schwarz, J.C.; Baisaeng, N.; Hoppel, M.; Löw, M.; Keck, C.M.; Valenta, C. Ultra-small NLC for improved dermal delivery of coenyzme Q10. Int. J. Pharm., 2013, 447(1-2), 213-217.
[http://dx.doi.org/10.1016/j.ijpharm.2013.02.037] [PMID: 23438979]
[67]
Lohan, S.B.; Bauersachs, S.; Ahlberg, S.; Baisaeng, N.; Keck, C.M.; Müller, R.H.; Witte, E.; Wolk, K.; Hackbarth, S.; Röder, B.; Lademann, J.; Meinke, M.C. Ultra-small lipid nanoparticles promote the penetration of coenzyme Q10 in skin cells and counteract oxidative stress. Eur. J. Pharm. Biopharm., 2015, 89, 201-207.
[http://dx.doi.org/10.1016/j.ejpb.2014.12.008] [PMID: 25500282]
[68]
Brugè, F.; Damiani, E.; Puglia, C.; Offerta, A.; Armeni, T.; Littarru, G.P.; Tiano, L. Nanostructured lipid carriers loaded with CoQ10: effect on human dermal fibroblasts under normal and UVA-mediated oxidative conditions. Int. J. Pharm., 2013, 455(1-2), 348-356.
[http://dx.doi.org/10.1016/j.ijpharm.2013.06.075] [PMID: 23850626]
[69]
Nguyen, T.A.; Friedman, A.J. Curcumin: a novel treatment for skin-related disorders. J. Drugs Dermatol., 2013, 12(10), 1131-1137.
[PMID: 24085048]
[70]
Esposito, E.; Ravani, L.; Mariani, P.; Contado, C.; Drechsler, M.; Puglia, C.; Cortesi, R. Curcumin containing monoolein aqueous dispersions: a preformulative study. Mater. Sci. Eng. C, 2013, 33(8), 4923-4934.
[http://dx.doi.org/10.1016/j.msec.2013.08.017] [PMID: 24094206]
[71]
Puglia, C.; Cardile, V.; Panico, A.M.; Crascì, L.; Offerta, A.; Caggia, S.; Drechsler, M.; Mariani, P.; Cortesi, R.; Esposito, E. Evaluation of monooleine aqueous dispersions as tools for topical administration of curcumin: characterization, in vitro and ex-vivo studies. J. Pharm. Sci., 2013, 102(7), 2349-2361.
[http://dx.doi.org/10.1002/jps.23605] [PMID: 23686742]
[72]
Esposito, E.; Ravani, L.; Mariani, P.; Huang, N.; Boldrini, P.; Drechsler, M.; Valacchi, G.; Cortesi, R.; Puglia, C. Effect of nanostructured lipid vehicles on percutaneous absorption of curcumin. Eur. J. Pharm. Biopharm., 2014, 86(2), 121-132.
[http://dx.doi.org/10.1016/j.ejpb.2013.12.011] [PMID: 24361485]
[73]
Esposito, E.; Sticozzi, C.; Ravani, L.; Drechsler, M.; Muresan, X.M.; Cervellati, F.; Cortesi, R.; Valacchi, G. Effect of new curcumin-containing nanostructured lipid dispersions on human keratinocytes proliferative responses. Exp. Dermatol., 2015, 24(6), 449-454.
[http://dx.doi.org/10.1111/exd.12696] [PMID: 25808217]
[74]
Esposito, E.; Drechsler, M.; Mariani, P.; Panico, A.M.; Cardile, V.; Crascì, L.; Carducci, F.; Graziano, A.C.E.; Cortesi, R.; Puglia, C. Nanostructured lipid dispersions for topical administration of crocin, a potent antioxidant from saffron (Crocus sativus L.). Mater. Sci. Eng. C, 2017, 71, 669-677.
[http://dx.doi.org/10.1016/j.msec.2016.10.045] [PMID: 27987758]
[75]
Xing, H.; Wang, H.; Wu, B.; Zhang, X. Lipid nanoparticles for the delivery of active natural medicines. Curr. Pharm. Des., 2017, 23(43), 6705-6713.
[http://dx.doi.org/10.2174/1381612824666171128105853] [PMID: 29189139]
[76]
Matias, I.; Wang, J.W.; Moriello, A.S.; Nieves, A.; Woodward, D.F.; Di Marzo, V. Changes in endocannabinoid and palmitoylethanolamide levels in eye tissues of patients with diabetic retinopathy and age-related macular degeneration. Prostaglandins Leukot. Essent. Fatty Acids, 2006, 75(6), 413-418.
[http://dx.doi.org/10.1016/j.plefa.2006.08.002] [PMID: 17011761]
[77]
Petrosino, S.; Iuvone, T.; Di Marzo, V. N-palmitoyl-ethanolamine: Biochemistry and new therapeutic opportunities. Biochimie, 2010, 92(6), 724-727.
[http://dx.doi.org/10.1016/j.biochi.2010.01.006] [PMID: 20096327]
[78]
Puglia, C.; Blasi, P.; Ostacolo, C.; Sommella, E.; Bucolo, C.; Platania, C.B.M.; Romano, G.L.; Geraci, F.; Drago, F.; Santonocito, D.; Albertini, B.; Campiglia, P.; Puglisi, G.; Pignatello, R. Innovative Nanoparticles Enhance N-Palmitoylethanolamide Intraocular Delivery. Front. Pharmacol., 2018, 9, 285.
[http://dx.doi.org/10.3389/fphar.2018.00285] [PMID: 29643808]
[79]
Fangueiro, J.F.; Calpena, A.C.; Clares, B.; Andreani, T.; Egea, M.A.; Veiga, F.J.; Garcia, M.L.; Silva, A.M.; Souto, E.B. Biopharmaceutical evaluation of epigallocatechin gallate-loaded cationic lipid nanoparticles (EGCG-LNs): In vivo, in vitro and ex vivo studies. Int. J. Pharm., 2016, 502(1-2), 161-169.
[http://dx.doi.org/10.1016/j.ijpharm.2016.02.039] [PMID: 26921515]
[80]
Arana, L.; Salado, C.; Vega, S.; Aizpurua-Olaizola, O.; de la Arada, I.; Suarez, T.; Usobiaga, A.; Arrondo, J.L.R.; Alonso, A.; Goñi, F.M.; Alkorta, I. Solid lipid nanoparticles for delivery of Calendula officinalis extract. Colloids Surf. B Biointerfaces, 2015, 135, 18-26.
[http://dx.doi.org/10.1016/j.colsurfb.2015.07.020] [PMID: 26231862]
[81]
Crandall, J.; Matragoon, S.; Khalifa, Y.M.; Borlongan, C.; Tsai, N.T.; Caldwell, R.B.; Liou, G.I. Neuroprotective and intraocular pressure-lowering effects of (-)Delta9-tetrahydrocannabinol in a rat model of glaucoma. Ophthalmic Res., 2007, 39(2), 69-75.
[http://dx.doi.org/10.1159/000099240] [PMID: 17284931]
[82]
El-Remessy, A.B.; Khalil, I.E.; Matragoon, S.; Abou-Mohamed, G.; Tsai, N.J.; Roon, P.; Caldwell, R.B.; Caldwell, R.W.; Green, K.; Liou, G.I. Neuroprotective effect of (-)Delta9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite. Am. J. Pathol., 2003, 163(5), 1997-2008.
[http://dx.doi.org/10.1016/S0002-9440(10)63558-4] [PMID: 14578199]
[83]
Punyamurthula, N.S.; Adelli, G.R.; Gul, W.; Repka, M.A.; ElSohly, M.A.; Majumdar, S. Ocular disposition of Δ8-tetrahydrocannabinol from various topical ophthalmic formulations. AAPS PharmSciTech, 2017, 18(6), 1936-1945.
[http://dx.doi.org/10.1208/s12249-016-0672-2] [PMID: 27905004]
[84]
Spalton, D.J. Posterior capsular opacification after cataract surgery. Eye (Lond.), 1999, 13(Pt 3b), 489-492.
[http://dx.doi.org/10.1038/eye.1999.127] [PMID: 10627830]
[85]
Zhang, W.; Li, X.; Ye, T.; Chen, F.; Sun, X.; Kong, J.; Yang, X.; Pan, W.; Li, S. Design, characterization, and in vitro cellular inhibition and uptake of optimized genistein-loaded NLC for the prevention of posterior capsular opacification using response surface methodology. Int. J. Pharm., 2013, 454(1), 354-366.
[http://dx.doi.org/10.1016/j.ijpharm.2013.07.032] [PMID: 23876384]
[86]
Zhang, W.; Liu, J.; Zhang, Q.; Li, X.; Yu, S.; Yang, X.; Kong, J.; Pan, W. Enhanced cellular uptake and anti-proliferating effect of chitosan hydrochlorides modified genistein loaded NLC on human lens epithelial cells. Int. J. Pharm., 2014, 471(1-2), 118-126.
[http://dx.doi.org/10.1016/j.ijpharm.2014.05.030] [PMID: 24858387]
[87]
Hartong, D.T.; Berson, E.L.; Dryja, T.P. Retinitis pigmentosa. Lancet, 2006, 368(9549), 1795-1809.
[http://dx.doi.org/10.1016/S0140-6736(06)69740-7] [PMID: 17113430]
[88]
Rotstein, N.P.; Miranda, G.E.; Abrahan, C.E.; German, O.L. Regulating survival and development in the retina: key roles for simple sphingolipids. J. Lipid Res., 2010, 51(6), 1247-1262.
[http://dx.doi.org/10.1194/jlr.R003442] [PMID: 20100817]
[89]
Strettoi, E.; Gargini, C.; Novelli, E.; Sala, G.; Piano, I.; Gasco, P.; Ghidoni, R. Inhibition of ceramide biosynthesis preserves photoreceptor structure and function in a mouse model of retinitis pigmentosa. Proc. Natl. Acad. Sci. USA, 2010, 107(43), 18706-18711.
[http://dx.doi.org/10.1073/pnas.1007644107] [PMID: 20937879]
[90]
Liu, R.; Liu, Z.; Zhang, C.; Zhang, B. Nanostructured lipid carriers as novel ophthalmic delivery system for mangiferin: improving in vivo ocular bioavailability. J. Pharm. Sci., 2012, 101(10), 3833-3844.
[http://dx.doi.org/10.1002/jps.23251] [PMID: 22767401]
[91]
Liu, Z.; Zhang, X.; Wu, H.; Li, J.; Shu, L.; Liu, R.; Li, L.; Li, N. Preparation and evaluation of solid lipid nanoparticles of baicalin for ocular drug delivery system in vitro and in vivo. Drug Dev. Ind. Pharm., 2011, 37(4), 475-481.
[http://dx.doi.org/10.3109/03639045.2010.522193] [PMID: 21054217]
[92]
Gupta, D.; Bleakley, B.; Gupta, R.K. Dragon’s blood: botany, chemistry and therapeutic uses. J. Ethnopharmacol., 2008, 115(3), 361-380.
[http://dx.doi.org/10.1016/j.jep.2007.10.018] [PMID: 18060708]
[93]
Hao, J.; Wang, X.; Bi, Y.; Teng, Y.; Wang, J.; Li, F.; Li, Q.; Zhang, J.; Guo, F.; Liu, J. Fabrication of a composite system combining solid lipid nanoparticles and thermosensitive hydrogel for challenging ophthalmic drug delivery. Colloids Surf. B Biointerfaces, 2014, 114, 111-120.
[http://dx.doi.org/10.1016/j.colsurfb.2013.09.059] [PMID: 24176890]

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      • 9. middleware::check_user_access:24
      • 10. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 11. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
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      • 11. middleware::check_user_access:24
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
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      Backtrace
      • 11. middleware::check_user_access:27
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
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      • 7: 314482634
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      • 11: 314482634
      • 12: 314482634
      • 13: 314482634
      • 14: 314482634
      • 15: 314482634
      Backtrace
      • 14. app/Models/UserAccess/UserAccess.php:784
      • 15. middleware::check_user_access:114
      • 16. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 18. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
    • SELECT at.type_name, p.copyright, p.publisher_location,m.month,y.year, a.publish_on, a.nid article_nid,a.article_id, a.pmid, a.issue_id, a.title, a.abstract,a.podcast,a.altmetric_score,a.altmetric_url,a.kudos_url, a.page_count, a.first_page, a.elocator, a.last_page, i.publication_date, a.file_name, a.file_path, a.doi, a.is_epub,a.epub_type, a.volume_id, a.is_uploaded, a.editor_choice, a.is_epub, j.image_file_name, a.article_no, a.art_type AS article_type, a.supplementary_filename,a.html_filename,a.prc_filename,a.epub_filename, a.graph_abs_lg_filename, a.graph_abs_sm_filename, a.oa_image_lg_filename, a.oa_image_sm_filename, j.journal_banner,a.animated_abstract,a.erratum_in,a.erratum_for, (CASE WHEN a.issue_id =0 THEN j.epub_price ELSE j.price END) AS sell_price, j.epub_price, j.nid AS jour_nid, j.title AS journal_title, j.issn, j.eissn,j.journal_id, j.subtitle AS jour_subtitle, v.volume_id,v.volume_name AS volume, v.year_id, i.title AS issue, i.month_id ,i.type issue_type, j.subtitle,j.formerly_title, ac.subtitle AS epub_title,a.crossmark_enabled,a.text_mining_urls,a.license_urls,a.created, a.receivedate, a.revisedate, a.acceptdate,js.js_title FROM article a LEFT JOIN article_section ac ON a.is_epub = ac.art_sec_id LEFT JOIN journal_section js ON a.js_id = js.js_id LEFT JOIN article_type at ON a.art_type = at.art_type_id LEFT JOIN issue i ON a.issue_id = i.issue_id LEFT JOIN month m ON m.id = i.month_id LEFT JOIN volume v ON v.volume_id = a.volume_id INNER JOIN year y ON y.id = v.year_id INNER JOIN journal j ON j.journal_id = a.journal_id INNER JOIN publisher p ON p.publisher_id = j.publisher_id WHERE a.article_id=98811
      13.83msalphaeurekaselec_live_10_06_2022Article.php#408
      Backtrace
      • 11. app/Models/Article.php:408
      • 12. app/Http/Controllers/ArticleController.php:2515
      • 13. app/Http/Controllers/ArticleController.php:2035
      • 14. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 15. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `journal` where `journal_id` = 25 limit 1
      1.21msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 25
      Backtrace
      • 14. app/Models/Journal.php:64
      • 15. app/Http/Controllers/ArticleController.php:2516
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select count(*) as aggregate from (select j.nid as journal_nid,j.flyer_link,j.title ,j.issn,j.eissn,j.keyword, j.journal_id as journal_id, j.subtitle, j.image_file_name,j.description,j.journal_insight_url,j.doi from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where j.journal_status=1 and subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=25) and sj.journal_id!=25 group by `j`.`nid`) as `aggregate_table`
      2.11msalphaeurekaselec_live_10_06_2022Subject.php#200
      Backtrace
      • 16. app/Models/Subject.php:200
      • 17. app/Http/Controllers/ArticleController.php:2517
      • 18. app/Http/Controllers/ArticleController.php:2035
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 20. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select j.nid as journal_nid,j.flyer_link,j.title ,j.issn,j.eissn,j.keyword, j.journal_id as journal_id, j.subtitle, j.image_file_name,j.description,j.journal_insight_url,j.doi from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where j.journal_status=1 and subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=25) and sj.journal_id!=25 group by `j`.`nid` order by `j`.`journal_id` asc limit 10 offset 0
      1.75msalphaeurekaselec_live_10_06_2022Subject.php#200
      Backtrace
      • 14. app/Models/Subject.php:200
      • 15. app/Http/Controllers/ArticleController.php:2517
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select count(*) as aggregate from (select v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `se`.`ebook_id` inner join `year` as `y` on `y`.`id` = `v`.`year_id` where subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=25) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      5.57msalphaeurekaselec_live_10_06_2022Subject.php#220
      Backtrace
      • 16. app/Models/Subject.php:220
      • 17. app/Http/Controllers/ArticleController.php:2518
      • 18. app/Http/Controllers/ArticleController.php:2035
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 20. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `se`.`ebook_id` inner join `year` as `y` on `y`.`id` = `v`.`year_id` where subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=25) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      10.78msalphaeurekaselec_live_10_06_2022Subject.php#220
      Backtrace
      • 14. app/Models/Subject.php:220
      • 15. app/Http/Controllers/ArticleController.php:2518
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `keywords` where `article_id` = '98811'
      5.32msalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 98811
      Backtrace
      • 13. app/Models/Keywords.php:43
      • 14. app/Http/Controllers/ArticleController.php:2519
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `article_citation` where `article_id` = '98811'
      34.5msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 98811
      Backtrace
      • 13. app/Models/Article.php:1570
      • 14. app/Http/Controllers/ArticleController.php:2520
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select CONCAT_WS(' ',au.first_name, ' ', ifnull(au.initials,''), ' ', au.last_name) as authors, CONCAT(au.last_name, IFNULL(CONCAT(' ', au.initials), ''), ' ', au.first_name) AS authorsRIS, CONCAT_WS(' ',au.last_name, ' ', ifnull(au.initials,''), ' ', au.first_name) as authorsCiteAs, CONCAT_WS(' ',au.first_name, IFNULL(CONCAT(' ', au.initials), ''), IFNULL(CONCAT(' ', au.last_name), '')) as authorsmodal , `au`.*, `af`.`ror_id`, `af`.`institution`, `af`.`department`, `af`.`country`, `af`.`city`, `af`.`address`, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.institution,','),''), ifnull(concat(af.department,','),''), ifnull(concat(af.address,','),''), ifnull(concat(af.city,','),''), ifnull(concat(af.country,','),''), ifnull(concat(af.postal_code,','),''), ifnull(concat(af.phone,','),''), ifnull(concat(af.fax,','),''))) SEPARATOR '|')) as `author_affiliation`, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.web_view,','),''))) SEPARATOR '|')) as `web_view` from `author` as `au` left join `author_affiliation` as `af` on `au`.`author_id` = `af`.`author_id` where `au`.`article_id` = '98811' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      30.43msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 98811
      Backtrace
      • 13. app/Models/Author.php:86
      • 14. app/Http/Controllers/ArticleController.php:2533
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select `bo`.* from `bundle_offer` as `bo` where `bo`.`bundle_status` = 'A' order by `bo`.`bundle_id` desc
      440μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2535
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select `subtitle` from `journal` where `continues_publication_journal` = 1
      740μsalphaeurekaselec_live_10_06_2022Article.php#1960
      Bindings
      • 0: 1
      Backtrace
      • 13. app/Models/Article.php:1960
      • 14. app/Http/Controllers/ArticleController.php:2062
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • Select j.subtitle, v.volume_id as volume_id,v.year_id,y.year as year,v.volume_name, v.total_no_of_issues, i.issue_id as issue_id,i.title as issue, i.publication_date as issue_pub_date from journal j join volume v on j.journal_id = v.journal_id join issue i on v.volume_id = i.volume_id join article a on a.issue_id = i.issue_id join year y on v.year_id = y.id where j.journal_id = 25 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      209msalphaeurekaselec_live_10_06_2022Issue.php#298
      Backtrace
      • 11. app/Models/Issue.php:298
      • 12. app/Http/Controllers/ArticleController.php:2068
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 1 and a.journal_id = 25 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      126msalphaeurekaselec_live_10_06_2022Article.php#528
      Backtrace
      • 13. app/Models/Article.php:528
      • 14. app/Http/Controllers/ArticleController.php:2070
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 4 and a.journal_id = 25 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      90.45msalphaeurekaselec_live_10_06_2022Article.php#528
      Backtrace
      • 13. app/Models/Article.php:528
      • 14. app/Http/Controllers/ArticleController.php:2071
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select pdf, html, epub, prc from `article_metrics` where `article_id` = 98811 limit 1
      21.05msalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 98811
      Backtrace
      • 14. app/Models/Article.php:744
      • 15. app/Http/Controllers/ArticleController.php:2091
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from content_by_diseases where content_id = 98811 and content_type = 'article' order by status desc limit 1
      11.25msalphaeurekaselec_live_10_06_2022Article.php#751
      Backtrace
      • 11. app/Models/Article.php:751
      • 12. app/Http/Controllers/ArticleController.php:2094
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `node_meta` where `nid` = 172565 limit 1
      330μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 172565
      Backtrace
      • 14. app/Models/Meta.php:30
      • 15. app/Http/Controllers/ArticleController.php:2101
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `bo`.* from `bundle_offer` as `bo` where `bo`.`bundle_status` = 'A' order by `bo`.`bundle_id` desc
      360μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2108
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `tbl_ht_submission` as `h` where `h`.`subtitle` = 'CMC' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      540μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CMC
      Backtrace
      • 13. app/Models/Article.php:2025
      • 14. app/Http/Controllers/ArticleController.php:2112
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '98811' and content_type = 'a' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      530μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2186
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '9351' and content_type = 'i' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      490μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2207
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '2572' and content_type = 'v' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      630μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2231
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314482634 and j.to_ip >=314482634 )) and ((j.from_date <= 1740773643 and j.to_date >= 1740773643 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2572) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314482634 and j.to_ip >=314482634 )) and ((j.from_date <= 1740773643 and j.to_date >= 1740773643 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2572) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314482634 and j.to_ip >=314482634 )) and ((j.from_date <= 1740773643 and j.to_date >= 1740773643 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 2572)
      32.53msalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2272
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314482634 and j.to_ip >=314482634 )) and ((j.from_date <= 1740773643 and j.to_date >= 1740773643 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9351) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314482634 and j.to_ip >=314482634 )) and ((j.from_date <= 1740773643 and j.to_date >= 1740773643 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9351) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314482634 and j.to_ip >=314482634 )) and ((j.from_date <= 1740773643 and j.to_date >= 1740773643 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 9351)
      1.04msalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2297
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314482634 and j.to_ip >=314482634 )) and ((j.from_date <= 1740773643 and j.to_date >= 1740773643 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 98811) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314482634 and j.to_ip >=314482634 )) and ((j.from_date <= 1740773643 and j.to_date >= 1740773643 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 98811) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 314482634 and j.to_ip >=314482634 )) and ((j.from_date <= 1740773643 and j.to_date >= 1740773643 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 98811)
      950μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2329
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `article` where `first_page` < '4681' and is_uploaded = 1 and issue_id = 9351 order by cast(first_page as SIGNED) desc limit 1
      1.76msalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 4681
      Backtrace
      • 14. app/Models/Article.php:1819
      • 15. app/Http/Controllers/ArticleController.php:2470
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `article` where `last_page` > '4696' and is_uploaded = 1 and issue_id = 9351 order by cast(first_page as SIGNED) asc limit 1
      12.23msalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 4696
      Backtrace
      • 14. app/Models/Article.php:1831
      • 15. app/Http/Controllers/ArticleController.php:2472
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `language_id` from `multilanguage` where `short_code` = 'en'
      320μsalphaeurekaselec_live_10_06_2022ArticleController.php#2497
      Bindings
      • 0: en
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2497
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `source_lang_label`, `target_lang_label` from `multilanguage_labels` where `target_lang_id` = 1
      330μsalphaeurekaselec_live_10_06_2022MultiLanguage.php#23
      Bindings
      • 0: 1
      Backtrace
      • 13. app/Models/MultiLanguage.php:23
      • 14. app/Http/Controllers/ArticleController.php:2498
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `id` from `multilanguage_article` where `article_id` = 98811 limit 1
      2.75msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 98811
      Backtrace
      • 16. app/Http/Controllers/ArticleController.php:2506
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 20. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 25 and `b`.`banner_from_date` <= 1740773643 and `b`.`banner_to_date` >= 1740773643 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      4.69msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 25
      • 3: 1740773643
      • 4: 1740773643
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 25 and `b`.`banner_from_date` <= 1740773643 and `b`.`banner_to_date` >= 1740773643 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      28.74msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 25
      • 3: 1740773643
      • 4: 1740773643
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='bbd2fb942cab3f468ebc6f9b693f5108'
      6.91msalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:291
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\MultiLanguage
    1MultiLanguage.php#?
    App\Models\MultiLangArticle
    1MultiLangArticle.php#?
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        ClearShow all
        Date ↕MethodURLData
        #12025-02-28 20:14:03GET/article/98811314362